DETERMINANTS OF PROMOTER-SPECIFIC ACTIVITY BY GLUCOCORTICOID RECEPTOR

Glucocorticoid receptor (GR) is expressed at essentially equal levels in almost ail tissues and cell types. Remarkably, glucocorticoids them selves regulate transcription in vivo in both a promoter- and tissue-s pecific manner. Thus, specific systems must be in place to regulate re ceptor action within certain cells and at certain promoters. To addres s two specific aspects of these systems, we have analyzed promoter-spe cific activity of GR using two different, well studied promoters (term ed simple and composite promoters) from which GR activates transcripti on. The simple promoter depends only on the receptor for glucocorticoi d-responsive transcriptional activation, while GR activity at the comp osite promoter depends on additional transcription factors. We have co mpared the action of several GR ligands at these promoters end demonst rate fundamental differences in the activities of these ligands on rec eptor activity. Furthermore, these compounds induce unique conformatio nal changes in receptor, resulting in promoter-specific receptor funct ion. We have identified critical amino acid residues within GR which, when mutated, genetically distinguish the action of GR at these promot ers. Taken together, the data indicate that the presence of only the r eceptor and the ligand is not sufficient to allow activation of transc ription. An additional system of regulation influences receptor action in both a tissue- and promoter-selective fashion, suggesting that mul tiple, regulated surfaces of the receptor respond to the cellular envi ronment and determine the spectrum of GR activities. These functional surfaces may be induced or regulated by ligand binding, by the DNA seq uence to which receptor is bound, or by the nonreceptor factors reside nt at the promoter or in the tissue.